8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(sulfinyl- and sulfonyl-containing acyl)hydrazides

ABSTRACT

This invention relates to 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(sulfinyl- and sulfonyl-containing acyl)hydrazides that are useful as prostaglandin antagonists and analgesic agents.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(sulfinyl-and sulfonyl-containing acyl)hydrazides that are useful pharmacologicalagents. These compounds are prostaglandin antagonists having analgesicactivity.

Analgesics are agents used in the treatment of pain and often are usefulin alleviating inflammation. The major classes of analgesics includenarcotic analgesics (or opiates) and analgesic-antipyretics such as thesalicylates. Although the efficacy of opiates in relieving pain iswell-established, the associated addiction liability is a distinctdisadvantage. Although salicylate and salicylate-like agents(non-steroidal antiinflammatory agents) are also efficacious inrelieving pain, they often exhibit undesirable side effects such asgastrointestinal irritation (as with aspirin), allergic response (aswith aspirin), or liver toxicity with extended use (as withacetaminophen). The compounds included in this invention are neitheropiates nor salicylates and may be expected not to exhibit thedisadvantages of either class of compound.

(b) Prior Art

The closest prior art discloses compounds of the following formula,wherein group B is carbonyl (CO) or sulfonyl (SO₂) and wherein A may bealkyl or substituted alkyl. The prior art does not, however, disclosenor anticipate the compounds of this invention. ##STR1##

More specifically, U.S. Pat. No. 3,534,019 discloses compounds in whichB and A together constitute "lower alkanoyl," and U.S. Pat. No.3,989,719 discloses compounds in which B and A together constitute"higher alkanoyl." Thus, U.S. Pat. Nos. '019 and '719 each disclosecompounds in which A is a hydrocarbon. The sulfoxide- andsulfone-containing compounds of this invention are not disclosed.

U.S. Pat. Nos. 4,045,442, 4,125,532 (division of '442), and 4,170,593(division of '532) disclose compounds in which B is carbonyl and A is(substituted amino)alkyl. The sulfur-containing compounds of thisinvention are not disclosed.

U.S. Pat. Nos. 3,917,649 and 3,992,375 (division of '649) disclosecompounds in which B is carbonyl or sulfonyl: where B is carbonyl, A maybe haloalkyl, alkenyl, or aryloxyalkyl; and where B is sulfonyl, A maybe alkyl, haloalkyl, aryl, or aralkyl. U.S. Pat. Nos. '649 and '375 thusdisclose compounds in which a sulfonyl group must be attached directlyto a hydrazine nitrogen, but do not disclose compounds in which B iscarbonyl and A contains sulfoxide or sulfone groups. Thus, the compoundsof this invention are structurally distinct from the prior art.

SUMMARY OF THE INVENTION

This invention relates to compounds of Formula I: ##STR2## wherein X isSO or SO₂ ; wherein R is alkyl containing from 1 to 6 carbon atoms,inclusive; and

wherein n is an integer from 1 to 4, inclusive.

Examples of alkyl of 1 to 6 carbon atoms, inclusive, are methyl, ethyl,propyl, butyl, pentyl, hexyl, and the isomeric forms thereof, generallyreferred to as lower alkyl.

DESCRIPTION OF THE INVENTION

The compounds of this invention may be prepared by the methodsillustrated in the following Schemes. Unless otherwise specified, thevarious substituents are defined as for Formula I, above. Scheme Aillustrates the preparation of sulfur-containing intermediates ofFormula IV (Formula I in which X is S).

SCHEME A

Compounds of Formula IV are prepared by at least two different routesfrom 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acidhydrazide (Formula II), the preparation of which is described in U.S.Pat. No. 3,534,019. In the first route, described in U.S. Pat. No.4,045,442, the hydrazide of Formula II is acylated to give intermediatesof Formula III. The preferred leaving group Y is a chlorine atom.

Intermediates of Formula III may be converted to intermediates ofFormula IV by several methods. For example, a preferred method involvesan initial reaction with an alkali metal hydrosulfide, followed byalkylation of the intermediate thiol. Preferred conditions includeinitial reaction of ##STR3## intermediate III with sodium hydrogensulfide in a chilled alcohol, such as methanol, followed by addition ofthe appropriate iodoalkane (i.e., R-I). Another method for preparingintermediates IV involves direct reaction of an alkanethiol (i.e., R-SH)with intermediates III in the presence of a base, such as a tertiaryamine.

In a second route used to prepare intermediates III, the hydrazide ofFormula II is acylated with appropriate acyl halides of Formula V in thepresence of a base. Preferred acylating conditions include reaction ofthe hydrazide (Formula II) and an acyl chloride (Formula V, Z=Cl) in anunreactive organic solvent, such as dichloromethane, containing atertiary amine, such as triethylamine. The acyl halides may be preparedby methods well known to those skilled in the art, as illustrated in thePreparations below.

Scheme B illustrates the preparation of sulfoxides of this invention,Formula VI (Formula I in which X is SO), and sulfones of this invention,Formula VII (Formula I in which X is SO₂).

SCHEME B

Compounds of Formulas VI and VII are each prepared by oxidizingintermediates of Formula IV, preferably using a peroxycarboxylic acid ina cooled solvent. Careful control of the oxidizing conditions permitspreparing sulfoxides VI ##STR4## without significant further oxidationto sulfones VII. Preferred conditions for preparing sulfoxides VIinclude oxidizing intermediates IV with an approximately equimolarquantity of m-chloroperoxybenzoic acid in an organic solvent, such asdichloromethane, at about 0° C. Oxidization is then quenched by addingaqueous sodium thiosulfate.

Sulfones VII may be prepared by two general methods. First,intermediates IV may be oxidized directly to sulfones VII. Preferredconditions for such a direct oxidation are similar to those describedabove for the corresponding sulfoxides VI, except that a two-fold molarquantity of m-chloroperoxybenzoic acid is used. Oxidization is similarlyquenched by adding aqueous sodium thiosulfate. Second, sulfoxides VI maybe oxidized to sulfones VII. Preferred conditions for such an oxidationare essentially identical to those used to form sulfoxides VI fromintermediates IV.

The preferred embodiments of this invention, as indicated by biologicalactivity in the following assays, are compounds according to Formula Iwherein X is SO₂. The most preferred embodiment of this invention is acompound according to Formula I wherein X is SO₂, R is ethyl, and n is 2(exemplified in Example 10 below).

The compounds are prostaglandin E₂ antagonists, as indicated by a guineapig ileum assay performed essentially as described by J. H, Sanner,Arch. int. Pharmacodyn, 180, 46 (1969). The compounds of this inventionexhibited analgesic activity in mice, as indicated by the PBQ-writhingassay. The activities of the compounds of this invention illustrated inthe examples were determined by the following methods.

Prostaglandin Antagonism Assay

Female albino guinea pigs weighing 200 to 500 grams were sacrificed bycervical dislocation. The ileum was quickly removed and placed in amodified Tyrode solution containing one-half the usual amount ofmagnesium ions. Segments of ileum about 2 cm long were cut and mountedin a 2- or 4-ml tissue bath containing the modified Tyrode solution, andthe solution was maintained at 37° and aerated with a gaseous mixture of95% oxygen and 5% carbon dioxide. Contractions were detectedisotonically. Submaximal contractions were obtained by adjusting thedose of prostaglandin E₂ (PGE₂) added to the bath. Two controlcontractions were obtained at 3.5 minute intervals. A solution orsuspension of the test compound in the bathing solution was thensubstituted for the original modified Tyrode solution. The testsuspension was kept in constant contact with the tissue for theremainder of the experiment, except for brief periods to drain the bathin preparation for rinsing with fresh test suspension. Three morecontractions were elicited for the PGE₂ agonist in the presence of thetest compound without interrupting the time sequence. The last two setsof treated responses were compared with the two sets of controlresponses. (The first set of treated responses was not used forcomparisons, being used only to maintain the timed sequence ofinjections during the period allowed for the tissue to becomeequilibrated with the antagonist). A compound was rated active if themean of contractions produced by the agonist was reduced 75% or more bythe test compound.

PBO-Writhing Assay

Male Charles River albino mice (CD-1(ICR)BR) weighing 20 to 30 gramswere used in this assay. Thirty minutes after subcutaneous orintragastric administration (0.1 ml per 10 g of body weight) or fifteenminutes after intracerebroventricular administration (5 mcl totalvolume), a 0.025% solution of phenylbenzoquinone (PBQ) was injectedintraperitoneally (0.1 ml per 10 g of body weight). Five minutes latereach mouse was placed in a glass beaker and the number of writhesoccurring in the next ten minutes was counted. (A writhe consists ofdorsoflexion of the back, extension of the hindlimbs, and strongcontraction of the abdominal musculature.) The test compound wasconsidered to have produced analgesia in a mouse if the number ofwrithes elecited by PBQ was equal to or less than one-half the mediannumber of writhes recorded for the saline-treated control group of micethat day. Results were expressed as the number of mice out of a possibleten in which the test compound produced analgesia. If the initialscreening dose of 10 mg/kg inhibited writhing in greater than six of tenmice, the effect of additional doses of the compound on the writhingresponse was evaluated and an ED₅₀ was calculated.

By virtue of their analgesic activity, the compounds of Formula I areuseful in treating pain in mammals. A physician or veterinarian ofordinary skill can readily determine whether a subject is in pain.Regardless of the route of administration selected, the compounds of thepresent invention are formulated into pharmaceutically acceptable dosageforms by conventional methods known to those skilled in the art.Moreover, the compounds may be used in a suitable hydrated form.

The compounds can be administered in such oral dosage forms as tablets,capsules, pills, powders, granules, elixirs, or syrups. They may also beadministered intravascularly, intraperitoneally, subcutaneously,intramuscularly, or topically, using forms known to the pharmaceuticalart. In general, the preferred form of administration is oral. Aneffective but non-toxic quantity of the compound is employed intreatment. The dosage regimen for treating pain with the compounds ofthis invention is selected in accordance with a variety of factors,including the type, age, weight, sex, and medical condition of thepatient; the severity of the pain; the route of administration; and theparticular compound employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent or arrest the progress of the condition. Inso proceeding, the physician or veterinarian could employ relatively lowdoses at first and subsequently increase the dose until a maximumresponse is obtained. Dosages of the compounds of the invention may bein the range of about 0.1 to 100 mg/kg, preferably in the range of about0.5 to 5.0 mg/kg.

In the pharmaceutical compositions and methods of the present invention,the foregoing active ingredients will typically be administered inadmixture with suitable pharmaceutical diluents, excipients, or carriers(collectively referred to herein as "carrier" materials) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups, and the like, and consistentwith conventional pharmaceutical practices. For instance, for oraladministration in the form of tablets or capsules, the active drugcomponents may be combined with any oral non-toxic pharmaceuticallyacceptable inert carrier such as lactose, starch, surcrose, cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, andthe like; for oral administration in liquid form, the active drugcomponents may be combined with any oral non-toxic pharmaceuticallyacceptable inert carrier such as ethanol and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated in the mixture.Suitable binders include starch, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethylcellulose, polyethylene glycol, and waxes. Lubricants foruse in these dosage forms include boric acid, sodium benzoate, sodiumacetate, sodium chloride, and the like. Disintegrators include, withoutlimitation, starch, methylcellulose, agar, bentonite, guar gum, and thelike. Sweetening and flavoring agents and preservatives can also beincluded where appropriate.

The following preparations and examples further illustrate details forthe preparation of the compounds of this invention. The invention, whichis set forth in the foregoing disclosure, is not to be construed orlimited either in spirit or in scope by these examples. Those skilled inthe art will readily understand that known variations of the conditionsand processes of the following preparative procedures can be used toprepare these compounds. All temperatures are degrees Celsius unlessotherwise noted.

PREPARATION OF STARTING MATERIALS AND INTERMEDIATES Preparation 13-thiahexanoic acid

    CH.sub.3 (CH.sub.2).sub.2 SCH.sub.2 COOH

To a solution of 18.3 g of propanethiol in 200 ml of cold (ca.0°) 18%aqueous sodium hydroxide was added 20.8 g of chloroacetic acid in 100 mlof 18% aqueous sodium hydroxide. The mixture was heated at reflux fortwo hours, then cooled with ice and acidified to about pH 2 withsulfuric acid. The mixture was extracted three times with 250-mlportions of diethyl ether. The organic extracts were combined, thenwashed three times with 200-ml portions of water, dried over sodiumsulfate, filtered, and concentrated in vacuo to give the title compound.Structure assignment was supported by the nmr spectrum.

Preparation 2 3-thiahexanoyl chloride

    CH.sub.3 (CH.sub.2).sub.2 SCH.sub.2 CO-Cl

To a solution of 4.0 g of the title product of Preparation 1 in 20 ml oftoluene under nitrogen was added 5.2 ml of oxalyl chloride in fourportions. The solution was stirred at room temperature for about twentyhours and then concentrated in vacuo to the oily title compound, whichwas used in subsequent reactions without further purification orcharacterization.

Preparation 3 5-thiahexanoic acid

    CH.sub.3 S(CH.sub.2).sub.3 COOH

To a stirred solution of 18 g of methanethiol in 125 ml of 35% aqueoussodium hydroxide was added 18.28 g of 4-chlorobutyronitrile in absoluteethanol. The mixture was heated at reflux for about three hours, thencooled with ice and water and extracted three times with 150-ml portionsof diethyl ether. The aqueous phase was acidified to about pH 2 withsulfuric acid and extracted three times with 150-ml portions of diethulether. The organic extracts were combined, then washed three times with100-ml portions of water, dried over sodium sulfate, filtered, andconcentrated in vacuo to give the title compound. Structure assignmentwas supported by the nmr spectrum.

Preparation 4 5-thiahexanoyl chloride

    CH.sub.3 S(CH.sub.2).sub.3 CO-Cl

The title compound was prepared by the method of Preparation 2 using 4.2g of the title product of Preparation 3 instead of the title product ofPreparation 1.

Preparation 5 4-thiahexanoic acid

    CH.sub.3 CH.sub.2 SCH.sub.2 CH.sub.2 COOH

To a solution of 43.5 g of 3-mercaptopropanoic acid and 36 g of sodiumhydroxide in 50 ml of cold water was added dropwise 64 g ofdiethylsulfate. The mixture was heated at reflux for six hours, thenallowed to stand at room temperature for twenty hours. The solution wascooled with ice and acidified to about pH 2 with sulfuric acid, thenextracted four times with 200-ml portion of diethyl ether. The organicextracts were combined, washed twice with 200-ml portions of water,dried over sodium sulfate, filtered, and concentrated in vacuo to givethe title compound. Structure assignment was supported by the nmrspectrum.

Preparation 6 4-thiahexanoyl chloride

    CH.sub.3 CH.sub.2 SCH.sub.2 CH.sub.2 CO-Cl

The title compound was prepared by the method of Preparation 2 using 4.0g of the title product of Preparation 5 instead of the title product ofPreparation 1.

DESCRIPTION OF THE EMBODIMENTS Example 18-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[(propylthio)acetyl]hydrazide

Method A ##STR5##

To a stirred mixture of 7.6 g of8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acidhydrazide (see U.S. Pat. No. 3,534,019) and 3.6 ml of triethylamine in50 ml of cold (ca. 0°) dichloromethane was slowly added 4.0 g of thetitle product of Preparation 2. The mixture was then stirred for twentyhours at room temperature. The solution was then washed three times with50-ml portions of water, dried over sodium sulfate, filtered, andconcentrated in vacuo to give the title compound, m.p. 78°-81°.

Analysis. Calcd. for C₁₉ H₂₀ N₃ O₃ SCl: C, 56.22; H, 4.97; N, 10.35; S,7.90.

Found: C, 55.83; H, 4.81; N, 10.34; S, 7.96.

Example 2 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[(propylthio)acetyl]hydrazide

Method B

To a stirred mixture of 7.6 g of1-chloracetyl-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine(see U.S. Pat. No. 4,045,442) in 25 ml of cold (ca. 0°) methanol wasadded 2.8 g of sodium hydrogen sulfide, followed by 9.75 ml ofiodopropane. The mixture was allowed to warm to room temperature. Aftertwo hours the mixture was acidified to about pH 2 with 1N aqueoushydrochloric acid and extracted three times with 20-ml portions ofdichloromethane. The organic extracts were combined, then washed threetimes with 20-ml portions of water, dried over sodium sulfate, filtered,and concentrated in vacuo to give the title compound, which wasidentical to samples prepared as in Example 1.

Example 3 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[4-(methylthio)-1-oxobutyl]hydrazide ##STR6##

The title compound, m.p. 134°-137°, was prepared by the method ofExample 1 using the title product of Preparation 4 instead of the titleproduct of Preparation 2.

Analysis. Calcd. for C₁₉ H₂₀ N₃ O₃ SCl: C, 56.22; H, 4.97; N, 10.35; S,7.90. Found: C, 56.19; H, 5.02; N, 10.51; S, 7.95.

Example 4 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-(ethylthio)-1-oxopropyl]hydrazide ##STR7##

The title compound, m.p. 126°-129°, was prepared by the method ofExample 1 using the title product of Preparation 6 instead of the titleproduct of Preparation 2.

Analysis. Calcd. for C₁₉ H₂₀ N₃ O₃ SCl: C, 56.22; H, 4.97; N, 10.35; S,7.90. Found: C, 55.99, H, 4.74; N, 10.28; S, 8.00.

Example 5 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[(propylsulfinyl)acetyl]hydrazide ##STR8##

To a stirred solution of 1.0 g (2.5 mmole) of the title product ofExample 1 in 20 ml of cold (ca. 0°) dichloromethane was added 0.56 g(2.6 mmole) of 81% m-chloroperoxybenzoic acid. After about ninetyminutes, 5 ml of saturated aqueous sodium thiosulfate was added. Themixture was washed sequentially with three 20-ml portions of saturatedaqueous sodium bicarbonate and three 20-ml portions of water. Theorganic phase was dried over sodium sulfate, filtered, and concentratedin vacuo to give the title compound, m.p. 158°-160°.

Analysis. Calcd. for C₁₉ H₂₀ N₃ O₄ SCl: C, 54.08; H, 4.78; N, 9.96; S,7.60. Found: C, 53.91; H, 4.81; N, 10.01; S, 7.54.

Example 6 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[(propylsulfonyl)acetyl]hydrazide

Method A ##STR9##

The title compound, m.p. 173°-175°, was prepared by the method ofExample 5, except that 1.06 g (5.0 mmole) of 81% m-chloroperoxybenzoicacid was used to oxidize 1.09 g (2.7 mmole) of the title product ofExample 1.

Analysis. Calcd. for C₁₉ H₂₀ N₃ O₅ SCl: C, 52.11; H, 4.60; N, 9.60; S,7.32. Found: C, 52.21; H, 4.52; N, 9.69, S, 7.42.

EXAMPLE 7 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[(propylsulfonyl)acetyl]hydrazide

Method B

The title compound, identical with samples prepared as in Example 6, wasprepared by the method of Example 5, except that 0.5 g (1.2 mmole) ofthe title sulfoxide of Example 5 was further oxidized with 0.25 g (1.2mmole) of 81% m-chloroperoxybenzoic acid.

Example 8 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[4-(methylsulfonyl)-1-oxobutyl]hydrazide ##STR10##

The title compound, m.p. 198°-199°, was prepared by the method ofexample 6 using 1.05 g (4.9 mmole) of 81% m-chloroperoxybenzoic acid tooxidize 1.0 g (2.6 mmole) of the title compound of Example 3 instead ofthe title product of Example 1.

Analysis. Calcd. for C₁₉ H₂₀ N₃ O₅ SCl: C, 52.11; H, 4.60; N, 9.60; S,7.32. Found: C, 52.03; H, 4.55; N, 9.62; S, 7.39.

Example 9 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-(ethylsulfinyl)-1-oxopropyl]hydrazide ##STR11##

The title compound, m.p. 185°-188°, was prepared by the method ofExample 5 using 0.526 g (2.5 mmole) of 81% m-chloroperoxybenzoic acid tooxidize 1.0 g (2.5 mmole) of the title product of Example 4 instead ofthe tltle product of Example 1.

Analsis. Calcd. for C₁₉ H₂₀ N₃ O₄ SCl: C, 54.08; H, 4.78; N, 9.96; S,7.60. Found: C, 53.99; H, 4.82; N, 9.87; S, 7.64.

Example 10 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide ##STR12##

The title compound, m.p. 181°-184°, was prepared by the method ofExample 6 using 0.525 g (2.5 mmole) of 81% m-chloroperoxybenzoic acid tooxidize 0.5 g (1.2 mmole) of the title product of Example 4 instead ofthe title product of Example 1.

Analysis. Calcd. for C₁₉ H₂₀ N₃ O₅ SCl: C, 52.11; H, 4.60; N, 9.60; S,7.32. Found: C, 52.17; H, 4.62; N, 9.56; S, 7.66.

What is claimed is:
 1. A compound of the formula: ##STR13## wherein X isSO or SO₂ ; wherein R is alkyl containing from 1 to 6 carbon atoms,inclusive; andwherein n is an integer from 1 to 4, inclusive.
 2. Acompound according to claim 1 having the formula: ##STR14##
 3. Acompound according to claim 2, which is8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[(propylsulfinyl)acetyl]hydrazide.
 4. A compound according to claim 2,which is 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-(ethylsulfinyl)-1-oxopropyl]hydrazide.
 5. A compound according toclaim 1 having the formula: ##STR15##
 6. A compound according to claim5, which is 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[(propylsulfonyl)acetyl]hydrazide.
 7. A compound according to claim 5,which is 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide.
 8. A compound according toclaim 5, which is 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylicacid, 2-[4-(methylsulfonyl)-1-oxobutyl]hydrazide.
 9. A pharmaceuticalcomposition comprising at least one compound according to claim 1,together with one or more non-toxic pharmaceutically acceptablecarriers.
 10. A pharmaceutical composition according to claim 9 whereinsaid compound is 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylicacid, 2-[(propylsulfinyl)acetyl]hydrazide.
 11. A pharmaceuticalcomposition according to claim 9 wherein said compound is8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-(ethylsulfinyl)-1-oxopropyl]hydrazide.
 12. A pharmaceuticalcomposition according to claim 9 wherein said compound is8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[(propylsulfonyl)acetyl]hydrazide.
 13. A pharmaceutical compositionaccording to claim 9 wherein said compound is8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide.
 14. A pharmaceuticalcomposition according to claim 9 wherein said compound is8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[4-(methylsulfonyl)-1-oxobutyl]hydrazide.
 15. A method for treatingpain in mammals comprising administering a therapeutically effectiveamount of at least one compound of claim 1 to a mammal in need of suchtreatment.
 16. A method according to claim 15 wherein said compound is8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[(propylsulfinyl)acetyl]hydrazide.
 17. A method according to claim 15wherein said compound is8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-(ethylsulfinyl)-1-oxopropyl]hydrazide.
 18. A method according toclaim 15 wherein said compound is8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[(propylsulfonyl)acetyl]hydrazide.
 19. A method according to claim 15wherein said compound is8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide.
 20. A method according toclaim 15 wherein said compound is8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[4-methylsulfonyl)-1-oxobutyl]hydrazide.